1. Field of the Invention
This invention relates generally to the field of therapeutic agents that have anti-mycobacterial activity. More particularly, this invention relates to halogenated compounds that have anti-mycobacterium tuberculosis activity, therapeutic agents for treating tuberculosis and methods of treating tuberculosis.
2. Description of Related Art
Tuberculosis is the oldest documented infectious disease, and it remains an important global health problem. An estimated I billion people worldwide are infected with Mycobacterium tuberculosis; 8 to 10 million new tuberculosis cases occur each year, and the number of new cases is estimated to increase to 12 million in the year 2005. Inadequacy of diagnosis and prevention in addition to inefficient treatment programs account for uncontrolled infection in developing countries.
Therapies exist to treat tuberculosis, however tuberculosis is not entirely cured by present drug treatments. Current drugs can minimize relapse rates with optimal treatment. With the best available chemotherapy, tubercle bacilli are slowly disposed of or killed. The widespread use of some drugs, such as isoniazid, has resulted in the development of resistant strains such that current drugs fail to eradicate some Mycobacterial infections. Therefore new drugs with anti-mycobacterial action are essential to successfully treat tuberculosis infections.
Because Mycobacteria develop resistance to drugs, optimal anti-tuberculous therapies require the use of several drugs in combination. Mycobacterial populations contain spontaneous mutants that are resistant to drugs even prior to exposure. The frequency of such mutations can vary between 1 in less than 100 to 1 in greater than 10,000, depending upon the drug. Single drug therapy can inhibit the majority of organisms in an infected site, yet permit, and in fact encourage, uncontrolled growth of the resistant mutants. Early combination therapy with at least two drugs is the preferred method of preventing emergence of large resistant populations in the original tuberculous cavities. Some drugs are most valuable for their ability to suppress emergence of resistance during combination therapy. An example is p-aminosalicylic acid, which can delay development of streptomycin resistance.
Thus, anti-mycobacterial agents can be important not only for their own efficacy against susceptible organisms but for their ability to enhance effectiveness of other agents by controlling emergence of resistant populations, for example populations resistant to pyrazinamide. Pyrazinamide is a major drug used in the therapy of tuberculosis and the synthesis of pyrazinamide was described by Kushner et al, J. Am. Chem. Soc. 74:3617 (1952), and the compound was patented in 1954 as a tuberculostatic agent (U.S. Pat. No. 2,677,641 issued to Williams). When pyrazinamide is used alone resistance develops quickly, and for this reason it is usually administered in combination with other drugs such as isoniazid. Pyrazinamide is also hepatotoxic, which further limits its use as a therapeutic agent.
The development of new anti-mycobacterial agents presents a challenge of balancing toxicity to mycobateria with patient safety. Due to fluorine""s unique chemistry, fluorinated compounds offer some desirable features in pharmacological applications. For example, fluorine is the second smallest element, after hydrogen, and thus, fluorine closely mimics hydrogen at enzyme receptor sites. Fluorine""s high electronegativity typically alters chemical reactivity at these enzyme sites, and enzyme deactivation can result. However, high electronegativity also increases oxidative and thermal stability as a Cxe2x80x94F bond is stronger than a Cxe2x80x94H bond, which can also affect enzymatic activity. In some cases (e.g., 5-fluorouracil), the specific location of a xe2x80x9cdeceptorxe2x80x9d fluorine instead of hydrogen blocks, an essential biochemical reaction. The presence of fluorine may also promote lipid solubility, thereby enhancing drug absorption and transport rates in vivo.
Fluorinated organic molecules can be effective in the treatment of a variety of disorders. However, fluorination of compounds for the treatment of M. tuberculosis has not previously been successful. Isoniazid is one of the most active drugs for the treatment of tuberculosis. Fluorination of the pyridine ring of isoniazid resulted in drastically decreasing activity against M. tuberculosis. 
The global resurgence of tuberculosis and development of drug resistant populations have rekindled the need for and interest in the development of new anti-tubercular drugs. However no new anti-tuberculosis agents have been developed since the introduction of rifampin into clinical use. There continues to be a need for new compounds with high efficacy in anti-tuberculosis activity for use as therapeutic agents.
These needs are met by the halogenated compounds of this invention, which possess high anti-tuberculosis activity or are useful as intermediates in the manufacture of such compounds.
In one embodiment of this invention, a class of compounds which possess high anti-tuberculosis activity includes:
a halogenated compound having Structure I or a pharmaceutically acceptable salt thereof: 
wherein X1 is a halogen and X2 is a second halogen or hydrogen, and Y is sulfur or oxygen; and, a halogenated compound having Structure II: 
or a pharmaceutically acceptable salt thereof.
In another embodiment of this invention, a class of compounds which possess high anti-tuberculosis activity includes: a halogenated compound having Structure IV or a pharmaceutically acceptable salt thereof: 
wherein X1 is a halogen and X2 is a second halogen or hydrogen; a halogenated compound having Structure V or pharmaceutically acceptable salt thereof: 
wherein X is a halogen; and a halogenated compound having Structure VI: 
or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention, is a composition, which possess high anti-tuberculosis activity comprising any one of the halogenated compounds of this invention and a pharmaceutically acceptable binder, wherein the halogenated compound has anti-mycobacterium activity.
A still further embodiment of this invention is a method of treating a mammal infected with a Mycobacterium, comprising administering to the mammal a non-toxic, effective amount of a composition comprising any one of the halogenated compounds of this invention and a pharmaceutically acceptable binder, wherein the halogenated compound has anti-mycobacterium activity.
A still further embodiment of this invention is a halogenated compound having Structure III: 
wherein the compound of Structure III is useful as an intermediate in the manufacture of compounds of Structure II.